低氧诱导靶基因GBP2促进肾透明细胞癌进展的机制研究

Clear cell renal cell carcinoma (ccRCC) is the most common renal malignancy and a devastating type of cancer, responsible for approximately 75% of cases of kidney cancer. The discovery and identification of novel oncogenes of ccRCC is crucial to elucidate its pathogenesis. According to the latest genomics data, we have screened out , a new potential oncogene, GBP2. However, up to now, the biological function of GBP2 in cancer remains unclear. Previous research and our recent preliminary data showed that the mRNA and protein levels of GBP2 were significantly upregulated in the ccRCC tissues compared to the adjacent normal controls. Interference with GBP2 expression can inhibit the growth and invasion of tumor cells. And we found that overexpression of GBP2 induced by hypoxia can promote the epithelial mesenchymal transformation (EMT) of tumor cells. Therefore we propose current study to further determine the role of GBP2 in tumor pathogenesis, particularly renal cell cancer. In addition, we will investigate the molecular mechanisms by which GBP2 promotes ccRCC growth and metastasis. This study will facilitate our understanding of GBP2 in the pathogenesis of ccRCC, and establish HIF2A/GBP2/EMT pathway as a candidate target for treating clear cell renal cell carcinoma patients.

肾透明细胞癌(ccRCC)是肾脏中最常见及进展最快的恶性肿瘤，发现、鉴定ccRCC的新型致癌基因对阐明其发病机理至关重要。通过整合分析最新的基因组学数据，我们筛选出全新的潜在癌基因GBP2，但其在ccRCC发展中的作用仍不清楚。为揭示GBP2的功能，我们在前期预实验中，通过敲除或过表达实验，发现GBP2可促进肿瘤细胞的增殖及侵袭迁移；而在分子机制初步探索中，我们发现低氧可诱导GBP2的表达，而GBP2高表达可促进肿瘤细胞发生上皮间质转化（EMT）。基于此，本项目拟在分子水平、细胞水平、小鼠荷瘤模型和临床样本上，深入研究GBP2在ccRCC中的生物学功能，揭示HIF2A/GBP2/EMT通路促进肿瘤进展的分子机制。研究成果或为我们理解ccRCC进展、转移分子机制，寻找治疗ccRCC的新靶点提供重要的实验证据和理论支撑。

肾癌是一组发生于肾脏的异质性肿瘤，属于全球十大恶性肿瘤之一。其中，肾透明细胞癌(ccRCC)是肾脏中最常见及进展最快的恶性肿瘤。发现、鉴定肾透明细胞癌的新型致癌基因对阐明其发病机理至关重要。GBP2 属于 GTP 酶超家族中的一员，可被干扰素 IFN-gamma 诱导表达，其编码蛋白可水解 GTP 为 GDP。近期的研究表明，GBP2的表达与胃癌、食管癌的进展及恶性预后相关，但GBP2 在肾细胞癌中功能尚未完全阐明。本研究旨在探讨GBP2在肾透明细胞癌中生物学功能及潜在的分子机制。通过免疫组化、免疫印迹等方法，我们发现在肾癌组织、肾癌细胞系中GBP2高表达；结合肿瘤样本临床特征分析发现高表达的GBP2与肿瘤分级、淋巴结转移、远处转移及恶性预后显著相关。功能实验分析发现过表达GBP2促进肿瘤细胞的增殖、迁移及成瘤，而干扰GBP2后上述结果相反。在机制研究方面，通过数据分析发现，GBP2的表达与肿瘤免疫抑制评分呈显著正相关。而进一步转录组测序发现干扰GBP2显著改变IFN-gamma通路活性，相关性分析及免疫印迹实验证实GBP2与IFN通路关键转录因子STAT1/3蛋白协同表达。综上提示，GBP2可能是肾透明细胞癌的恶性预后分子，通过IFN-gamma-STAT1/3通路参与肿瘤免疫抑制微环境的形成。